Metabolic Dysfunction-Associated Steatohepatitis (MASH): Understanding the Complexities of Liver Disease
Formerly known as nonalcoholic steatohepatitis, metabolic dysfunction-associated steatohepatitis (MASH) is an inflammatory disease characterized by liver scarring or fibrosis that progressively impairs liver function.
MASH is a major risk factor for cirrhosis and liver cancer, making it the second leading cause of liver transplants in the United States after cirrhosis caused by chronic hepatitis C infection. With limited treatment options available, understanding the pathological processes driving MASH is essential for developing effective therapies.
In a groundbreaking study published recently in PNAS, a team of scientists from Sanford Burnham Prebys, the University of California San Diego School of Medicine, and other institutions shed light on the intricate interplay between diseased liver cells and macrophages – white blood cells crucial for immune response and tissue repair.
Dr. Debanjan Dhar, an associate professor in the Cancer Genome and Epigenetics Program at Sanford Burnham Prebys, led the study alongside Dr. David Brenner, the president and CEO of Sanford Burnham Prebys, and Dr. Christopher Glass, a professor of cellular and molecular medicine at UC San Diego. The first author of the study is Dr. Souradipta Ganguly, a postdoctoral research fellow at UC San Diego and Sanford Burnham Prebys.
The research uncovered that the mix of macrophages present in MASH varies depending on the disease’s progression or regression. Crucially, the team identified specific macrophage subpopulations essential for resolving MASH and liver fibrosis, a condition where extensive scarring hinders the liver’s normal function and repair mechanisms.
“In MASH, Kupffer cells, a specific type of liver-resident macrophage, are replaced by four distinct macrophage subpopulations. During disease regression, two lipid-associated macrophage subpopulations dominate and express TREM2, a receptor pivotal in regulating cell survival, proliferation, and anti-inflammatory responses,” explained Dr. Brenner.
“The presence of TREM2+ macrophages during regression is pivotal in slowing MASH progression, reducing inflammation, and resolving liver fibrosis. Conversely, lacking these macrophages allows the disease to advance unabated.”
Notably, MASH often manifests no discernible symptoms in its early stages, contributing to its prevalence in the U.S. The American Liver Foundation estimates that 80 to 100 million Americans have fatty liver disease, a precursor to MASH, cirrhosis, and other severe liver complications – often exacerbated by conditions like obesity.
Approximately 1.5% to 6.5% of U.S. adults are affected by MASH, with around 24% grappling with metabolic dysfunction-associated steatotic fatty liver disease, the condition preceding MASH, cirrhosis, and liver failure.
“Our findings underscore the critical role of lipid-associated macrophages expressing TREM2 in driving reparative functions and phasing out scar tissue, safeguarding the liver from fibrosis,” noted Dr. Dhar.
The researchers suggest that leveraging a TREM2 agonist, a substance mimicking the receptor’s function, could hold promise in MASH and fibrosis therapy. Combined with lifestyle modifications, weight loss, or bariatric surgery, this approach may promote disease regression and alleviate liver damage in affected individuals.
“With only one approved MASH treatment available, newly sanctioned earlier this year, exploring additional therapeutic avenues is paramount given the escalating burden of liver disease in the U.S. and globally,” Dr. Glass emphasized.
The study’s other authors from UC San Diego, Cincinnati Children’s Hospital Medical Center, and Janssen Research & Development in San Diego collaborated in unraveling the nuances of MASH pathology and macrophage dynamics.
Supported by various grants from the National Institutes of Health (NIH), the research received funding from multiple sources to delve deeper into MASH etiology and potential treatment modalities.
As the global prevalence of liver diseases continues to rise, unravelling the complexities of conditions like MASH sheds light on novel therapeutic avenues and underscores the importance of ongoing research and clinical innovation in liver health.
By delving into the intricate interplay between liver cells, immune response, and disease progression, researchers are paving the way for targeted therapies to address the multifaceted challenges posed by MASH and liver fibrosis.
As the medical community strives to overcome the obstacles posed by liver diseases, ongoing collaborations, research initiatives, and innovative treatments offer hope for a future where liver health is safeguarded and liver diseases are effectively managed.
